2 Executive Summary Public opinion on the medical value of marijuana has been sharply divided. Some dismiss medical marijuana as a hoax that exploits our natural compassion for the sick; others claim it is a uniquely soothing medicine that has been withheld from patients through regulations based on false claims. Proponents of both views cite "scientific evidence" to support their views and have expressed those views at the ballot box in recent state elections. In January 1997, the White House Office of National Drug Control Policy (ONDCP) asked the Institute of Medicine (IOM) to conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids (see the Statement of Task on page 9). That review began in August 1997 and culminates with this report. The ONDCP request came in the wake of state "medical marijuana" initiatives. In November 1996, voters in California and Arizona passed referenda designed to permit the use of marijuana as medicine. Although Arizona's referendum was invalidated five months later, the referenda galvanized a national response. In November 1998, voters in six states (Alaska, Arizona, Colorado, Nevada, Oregon, and Washington) passed ballot initiatives in support of medical marijuana. (The Colorado vote will not count, however, because after the vote was taken a court ruling determined there had not been enough valid signatures to place the initiative on the ballot.) Can marijuana relieve health problems? Is it safe for medical use? Those straightforward questions are embedded in a web of social concerns, most of which lie outside the scope of this report. Controversies concerning the nonmedical use of marijuana spill over into the medical marijuana debate and obscure the real state of scientific knowledge. In contrast with the many disagreements bearing on social issues, the study team found substantial consensus among experts in the relevant disciplines on the scientific evidence about potential medical uses of marijuana. This report summarizes and analyzes what is known about the medical use of marijuana; it emphasizes evidence-based medicine (derived from knowledge and experience informed by rigorous scientific analysis), as opposed to belief-based medicine (derived from judgment, intuition, and beliefs untested by rigorous science). Throughout this report, marijuana refers to unpurified plant substances, including leaves or flower tops whether consumed by ingestion or smoking. References to the "effects of marijuana" should be understood to include the composite effects of its various components; that is, the effects of tetrahydrocannabinol (THC), which is the primary psychoactive ingredient in marijuana, are included among its effects, but not all the effects of marijuana are necessarily due to THC. Cannabinoids are the group of compounds related to THC, whether found in the marijuana plant, in animals, or synthesized in chemistry laboratories.

3 Three focal concerns in evaluating the medical use of marijuana are: 1. Evaluation of the effects of isolated cannabinoids; 2. Evaluation of the risks associated with the medical use of marijuana; and 3. Evaluation of the use of smoked marijuana. EFFECTS OF ISOLATED CANNABINOIDS Cannabinoid Biology Much has been learned since the 1982 IOM report Marijuana and Health. Although it was clear then that most of the effects of marijuana were due to its actions on the brain, there was little information about how THC acted on brain cells (neurons), which cells were affected by THC, or even what general areas of the brain were most affected by THC. In addition, too little was known about cannabinoid physiology to offer any scientific insights into the harmful or therapeutic effects of marijuana. That all changed with the identification and characterization of cannabinoid receptors in the 1980s and 1990s. During the past 16 years, science has advanced greatly and can tell us much more about the potential medical benefits of cannabinoids. Conclusion: At this point, our knowledge about the biology of marijuana and cannabinoids allows us to make some general conclusions: o o o o o Cannabinoids likely have a natural role in pain modulation, control of movement, and memory. The natural role of cannabinoids in immune systems is likely multi-faceted and remains unclear. The brain develops tolerance to cannabinoids. Animal research demonstrates the potential for dependence, but this potential is observed under a narrower range of conditions than with benzodiazepines, opiates, cocaine, or nicotine. Withdrawal symptoms can be observed in animals but appear to be mild compared to opiates or benzodiazepines, such as diazepam (Valium). Conclusion: The different cannabinoid receptor types found in the body appear to play different roles in normal human physiology. In addition, some effects of cannabinoids appear to be independent of those receptors. The variety of mechanisms through which cannabinoids can influence human physiology underlies the variety of potential therapeutic uses for drugs that might act selectively on different cannabinoid systems. Recommendation 1: Research should continue into the physiological effects of synthetic and plant-derived cannabinoids and the natural function of cannabinoids found in the body. Because different cannabinoids appear to

4 have different effects, cannabinoid research should include, but not be restricted to, effects attributable to THC alone. Efficacy of Cannabinoid Drugs The accumulated data indicate a potential therapeutic value for cannabinoid drugs, particularly for symptoms such as pain relief, control of nausea and vomiting, and appetite stimulation. The therapeutic effects of cannabinoids are best established for THC, which is generally one of the two most abundant of the cannabinoids in marijuana. (Cannabidiol is generally the other most abundant cannabinoid.) The effects of cannabinoids on the symptoms studied are generally modest, and in most cases there are more effective medications. However, people vary in their responses to medications, and there will likely always be a subpopulation of patients who do not respond well to other medications. The combination of cannabinoid drug effects (anxiety reduction, appetite stimulation, nausea reduction, and pain relief) suggests that cannabinoids would be moderately well suited for particular conditions, such as chemotherapy-induced nausea and vomiting and AIDS wasting. Defined substances, such as purified cannabinoid compounds, are preferable to plant products, which are of variable and uncertain composition. Use of defined cannabinoids permits a more precise evaluation of their effects, whether in combination or alone. Medications that can maximize the desired effects of cannabinoids and minimize the undesired effects can very likely be identified. Although most scientists who study cannabinoids agree that the pathways to cannabinoid drug development are clearly marked, there is no guarantee that the fruits of scientific research will be made available to the public for medical use. Cannabinoidbased drugs will only become available if public investment in cannabinoid drug research is sustained and if there is enough incentive for private enterprise to develop and market such drugs. Conclusion: Scientific data indicate the potential therapeutic value of cannabinoid drugs, primarily THC, for pain relief, control of nausea and vomiting, and appetite stimulation; smoked marijuana, however, is a crude THC delivery system that also delivers harmful substances. Recommendation 2: Clinical trials of cannabinoid drugs for symptom management should be conducted with the goal of developing rapid-onset, reliable, and safe delivery systems. Influence of Psychological Effects on Therapeutic Effects The psychological effects of THC and similar cannabinoids pose three issues for the therapeutic use of cannabinoid drugs. First, for some patients--particularly older patients with no previous marijuana experience--the psychological effects are disturbing. Those

5 patients report experiencing unpleasant feelings and disorientation after being treated with THC, generally more severe for oral THC than for smoked marijuana. Second, for conditions such as movement disorders or nausea, in which anxiety exacerbates the symptoms, the antianxiety effects of cannabinoid drugs can influence symptoms indirectly. This can be beneficial or can create false impressions of the drug effect. Third, for cases in which symptoms are multifaceted, the combination of THC effects might provide a form of adjunctive therapy; for example, AIDS wasting patients would likely benefit from a medication that simultaneously reduces anxiety, pain, and nausea while stimulating appetite. Conclusion: The psychological effects of cannabinoids, such as anxiety reduction, sedation, and euphoria can influence their potential therapeutic value. Those effects are potentially undesirable for certain patients and situations and beneficial for others. In addition, psychological effects can complicate the interpretation of other aspects of the drug's effect. Recommendation 3: Psychological effects of cannabinoids such as anxiety reduction and sedation, which can influence medical benefits, should be evaluated in clinical trials. RISKS ASSOCIATED WITH MEDICAL USE OF MARIJUANA Physiological Risks Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, except for the harms associated with smoking, the adverse effects of marijuana use are within the range of effects tolerated for other medications. The harmful effects to individuals from the perspective of possible medical use of marijuana are not necessarily the same as the harmful physical effects of drug abuse. When interpreting studies purporting to show the harmful effects of marijuana, it is important to keep in mind that the majority of those studies are based on smoked marijuana, and cannabinoid effects cannot be separated from the effects of inhaling smoke from burning plant material and contaminants. For most people the primary adverse effect of acute marijuana use is diminished psychomotor performance. It is, therefore, inadvisable to operate any vehicle or potentially dangerous equipment while under the influence of marijuana, THC, or any cannabinoid drug with comparable effects. In addition, a minority of marijuana users experience dysphoria, or unpleasant feelings. Finally, the short-term immunosuppressive effects are not well established but, if they exist, are not likely great enough to preclude a legitimate medical use. The chronic effects of marijuana are of greater concern for medical use and fall into two categories: the effects of chronic smoking and the effects of THC. Marijuana smoking is associated with abnormalities of cells lining the human respiratory tract. Marijuana smoke, like tobacco smoke, is associated with increased risk of cancer, lung

6 damage, and poor pregnancy outcomes. Although cellular, genetic, and human studies all suggest that marijuana smoke is an important risk factor for the development of respiratory cancer, proof that habitual marijuana smoking does or does not cause cancer awaits the results of well-designed studies. Conclusion: Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory disease. Recommendation 4: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent. Marijuana Dependence and Withdrawal A second concern associated with chronic marijuana use is dependence on the psychoactive effects of THC. Although few marijuana users develop dependence, some do. Risk factors for marijuana dependence are similar to those for other forms of substance abuse. In particular, anti-social personality and conduct disorders are closely associated with substance abuse. Conclusion: A distinctive marijuana withdrawal syndrome has been identified, but it is mild and short lived. The syndrome includes restlessness, irritability, mild agitation, insomnia, sleep disturbance, nausea, and cramping. Marijuana as a "Gateway" Drug Patterns in progression of drug use from adolescence to adulthood are strikingly regular. Because it is the most widely used illicit drug, marijuana is predictably the first illicit drug most people encounter. Not surprisingly, most users of other illicit drugs have used marijuana first. In fact, most drug users begin with alcohol and nicotine before marijuana--usually before they are of legal age. In the sense that marijuana use typically precedes rather than follows initiation of other illicit drug use, it is indeed a "gateway" drug. But because underage smoking and alcohol use typically precede marijuana use, marijuana is not the most common, and is rarely the first, "gateway" to illicit drug use. There is no conclusive evidence that the drug effects of marijuana are causally linked to the subsequent abuse of other illicit drugs. An important caution is that data on drug use progression cannot be assumed to apply to the use of drugs for medical purposes. It does not follow from those data that if marijuana were available by prescription for medical use, the pattern of drug use would remain the same as seen in illicit use. Finally, there is a broad social concern that sanctioning the medical use of marijuana might increase its use among the general population. At this point there are no convincing data to support this concern. The existing data are consistent with the idea that this would

7 not be a problem if the medical use of marijuana were as closely regulated as other medications with abuse potential. Conclusion: Present data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse. However, this question is beyond the issues normally considered for medical uses of drugs and should not be a factor in evaluating the therapeutic potential of marijuana or cannabinoids. USE OF SMOKED MARIJUANA Because of the health risks associated with smoking, smoked marijuana should generally not be recommended for long-term medical use. Nonetheless, for certain patients, such as the terminally ill or those with debilitating symptoms, the long-term risks are not of great concern. Further, despite the legal, social, and health problems associated with smoking marijuana, it is widely used by certain patient groups. Recommendation 5: Clinical trials of marijuana use for medical purposes should be conducted under the following limited circumstances: trials should involve only short-term marijuana use (less than six months), should be conducted in patients with conditions for which there is reasonable expectation of efficacy, should be approved by institutional review boards, and should collect data about efficacy. The goal of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the possible development of nonsmoked rapid-onset cannabinoid delivery systems. However, it will likely be many years before a safe and effective cannabinoid delivery system, such as an inhaler, is available for patients. In the meantime there are patients with debilitating symptoms for whom smoked marijuana might provide relief. The use of smoked marijuana for those patients should weigh both the expected efficacy of marijuana and ethical issues in patient care, including providing information about the known and suspected risks of smoked marijuana use. Recommendation 6: Short-term use of smoked marijuana (less than six months) for patients with debilitating symptoms (such as intractable pain or vomiting) must meet the following conditions: o o o o failure of all approved medications to provide relief has been documented, the symptoms can reasonably be expected to be relieved by rapidonset cannabinoid drugs, such treatment is administered under medical supervision in a manner that allows for assessment of treatment effectiveness, and involves an oversight strategy comparable to an institutional review board process that could provide guidance within 24 hours of a

8 submission by a physician to provide marijuana to a patient for a specified use. Until a nonsmoked rapid-onset cannabinoid drug delivery system becomes available, we acknowledge that there is no clear alternative for people suffering from chronic conditions that might be relieved by smoking marijuana, such as pain or AIDS wasting. One possible approach is to treat patients as n-of-1 clinical trials (single-patient trials), in which patients are fully informed of their status as experimental subjects using a harmful drug delivery system and in which their condition is closely monitored and documented under medical supervision, thereby increasing the knowledge base of the risks and benefits of marijuana use under such conditions. STATEMENT OF TASK The study will assess what is currently known and not known about the medical use of marijuana. It will include a review of the science base regarding the mechanism of action of marijuana, an examination of the peer-reviewed scientific literature on the efficacy of therapeutic uses of marijuana, and the costs of using various forms of marijuana versus approved drugs for specific medical conditions (e.g., glaucoma, multiple sclerosis, wasting diseases, nausea, and pain). The study will also include an evaluation of the acute and chronic effects of marijuana on health and behavior; a consideration of the adverse effects of marijuana use compared with approved drugs; an evaluation of the efficacy of different delivery systems for marijuana (e.g., inhalation vs. oral); an analysis of the data concerning marijuana as a gateway drug; and an examination of the possible differences in the effects of marijuana due to age and type of medical condition. Specific Issues Specific issues to be addressed fall under three broad categories: science base, therapeutic use, and economics. Science Base Review of the neuroscience related to marijuana, particularly the relevance of new studies on addiction and craving Review of the behavioral and social science base of

9 marijuana use, particularly an assessment of the relative risk of progression to other drugs following marijuana use Review of the literature determining which chemical components of crude marijuana are responsible for possible therapeutic effects and for side effects Therapeutic Use Evaluation of any conclusions on the medical use of marijuana drawn by other groups Efficacy and side effects of various delivery systems for marijuana compared to existing medications for glaucoma, wasting syndrome, pain, nausea, or other symptoms Differential effects of various forms of marijuana that relate to age or type of disease Economics Costs of various forms of marijuana compared with costs of existing medications for glaucoma, wasting syndrome, pain, nausea, or other symptoms Assessment of differences between marijuana and existing medications in terms of access and availability RECOMMENDATIONS Recommendation 1: Research should continue into the physiological effects of synthetic and plant-derived cannabinoids and the natural function of cannabinoids found in the body. Because different cannabinoids appear to have different effects, cannabinoid research should include, but not be restricted to, effects attributable to THC alone. Scientific data indicate the potential therapeutic value of cannabinoid drugs for pain relief, control of nausea and vomiting, and appetite stimulation. This value would be enhanced by a rapid onset of drug effect. Recommendation 2: Clinical trials of cannabinoid drugs for symptom management should be conducted with the goal of

10 developing rapid-onset, reliable, and safe delivery systems. The psychological effects of cannabinoids are probably important determinants of their potential therapeutic value. They can influence symptoms indirectly which could create false impressions of the drug effect or be beneficial as a form of adjunctive therapy. Recommendation 3: Psychological effects of cannabinoids such as anxiety reduction and sedation, which can influence medical benefits, should be evaluated in clinical trials. Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory diseases, but the data that could conclusively establish or refute this suspected link have not been collected. Recommendation 4: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent. Because marijuana is a crude THC delivery system that also delivers harmful substances, smoked marijuana should generally not be recommended for medical use. Nonetheless, marijuana is widely used by certain patient groups, which raises both safety and efficacy issues. Recommendation 5: Clinical trials of marijuana use for medical purposes should be conducted under the following limited circumstances: trials should involve only short-term marijuana use (less than six months), should be conducted in patients with conditions for which there is reasonable expectation of efficacy, should be approved by institutional review boards, and should collect data about efficacy. If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid

11 delivery systems. Recommendation 6: Short-term use of smoked marijuana (less than six months) for patients with debilitating symptoms (such as intractable pain or vomiting) must meet the following conditions: failure of all approved medications to provide relief has been documented, the symptoms can reasonably be expected to be relieved by rapid-onset cannabinoid drugs, such treatment is administered under medical supervision in a manner that allows for assessment of treatment effectiveness, and involves an oversight strategy comparable to an institutional review board process that could provide guidance within 24 hours of a submission by a physician to provide marijuana to a patient for a specified use.

12 1 Introduction This report summarizes and analyzes what is known about the medical use of marijuana; it emphasizes evidence-based medicine (derived from knowledge and experience informed by rigorous scientific analysis), as opposed to belief-based medicine (derived from judgment, intuition, and beliefs untested by rigorous science). Scientific data on controversial subjects are commonly misinterpreted, overinterpreted, and misrepresented, and the medical marijuana debate is no exception. We have tried to present the scientific studies in such a way as to reveal their strengths and limitations. One of the goals of this report is to help people to understand the scientific data, including the logic behind the scientific conclusions, so it goes into greater detail than previous reports on the subject. In many cases, we have explained why particular studies are inconclusive and what sort of evidence is needed to support particular claims about the harms or benefits attributed to marijuana. Ideally, this report will enable the thoughtful reader to interpret new information about marijuana that will continue to emerge rapidly well after this report is published. Can marijuana relieve health problems? Is it safe for medical use? Those straightforward questions are embedded in a web of social concerns, which lie outside the scope of this report. Controversies concerning nonmedical use of marijuana spill over onto the medical marijuana debate and tend to obscure the real state of scientific knowledge. In contrast with the many disagreements bearing on the social issues, the study team found substantial consensus, among experts in the relevant disciplines, on the scientific evidence bearing on potential medical use. This report analyzes science, not the law. As in any policy debate, the value of scientific analysis is that it can provide a foundation for further discussion. Distilling scientific evidence does not in itself solve a policy problem. What it can do is illuminate the common ground, bringing to light fundamental differences out of the shadows of misunderstanding and misinformation that currently prevail. Scientific analysis cannot be the end of the debate, but it should at least provide the basis for an honest and informed discussion. Our analysis of the evidence and arguments concerning the medical use of marijuana focuses on the strength of the supporting evidence and does not refer to the motivations of people who put forth the evidence and arguments. That is, it is not relevant to scientific validity whether an argument is put forth by someone who believes that all marijuana use should be legal or by someone who believes that any marijuana use is highly damaging to individual users and to society as a whole. Nor does this report comment on the degree to which scientific analysis is compatible with current regulatory policy. Although many have argued that current drug laws pertaining to marijuana are inconsistent with scientific

13 data, it is important to understand that decisions about drug regulation are based on a variety of moral and social considerations, as well as on medical and scientific ones. Even when a drug is used only for medical purposes, value judgments affect policy decisions concerning its medical use. For example, the magnitude of a drug's expected medical benefit affects regulatory judgments about the acceptability of risks associated with its use. Also, although a drug is normally approved for medical use only on proof of its "safety and efficacy," patients with life-threatening conditions are sometimes (under protocols for "compassionate use") allowed access to unapproved drugs whose benefits and risks are uncertain. Value judgments play an even more substantial role in regulatory decisions concerning drugs, such as marijuana, that are sought and used for nonmedical purposes. Then policymakers must take into account not only the risks and benefits associated with medical use but also possible interactions between the regulatory arrangements governing medical use and the integrity of the legal controls set up to restrict nonmedical use. It should be clear that many elements of drug control policy lie outside the realm of biology and medicine. Ultimately, the complex moral and social judgments that underlie drug control policy must be made by the American people and their elected officials. A goal of this report is to evaluate the biological and medical factors that should be taken into account in making those judgments. HOW THIS STUDY WAS CONDUCTED Information was gathered through scientific workshops, site visits, analysis of the relevant scientific literature, and extensive consultation with biomedical and social scientists. The three 2-day workshops--in Irvine, California; New Orleans, Louisiana; and Washington, D.C.--were open to the public and included scientific presentations and reports, mostly from patients and their families, about their experiences with and perspectives on the medical use of marijuana. Scientific experts in various fields were selected to talk about the latest research on marijuana, cannabinoids, and related topics (listed in Appendix B). Selection of the experts was based on recommendations by their peers, who ranked them among the most accomplished scientists and the most knowledgeable about marijuana and cannabinoids in their own fields. In addition, advocates for (John Morgan) and against (Eric A. Voth) the medical use of marijuana were invited to present scientific evidence in support of their positions. Information presented at the scientific workshops was supplemented by analysis of the scientific literature and evaluating the methods used in various studies and the validity of the authors' conclusions. Different kinds of clinical studies are useful in different ways: results of a controlled double-blind study with adequate sample sizes can be expected to apply to the general population from which study subjects were drawn; an isolated case report can suggest further studies but cannot be presumed to be broadly applicable; and survey data can be highly informative but are generally limited by the need to rely on self-reports of drug use and on unconfirmed medical diagnoses. This report relies mainly on the most relevant and methodologically rigorous studies available and treats the results

14 of more limited studies cautiously. In addition, study results are presented in such a way as to allow thoughtful readers to judge the results themselves. The Institute of Medicine (IOM) appointed a panel of nine experts to advise the study team on technical issues. These included neurology and the treatment of pain (Howard Fields); regulation of prescription drugs (J. Richard Crout); AIDS wasting and clinical trials (Judith Feinberg); treatment and pathology of multiple sclerosis (Timothy Vollmer); drug dependence among adolescents (Thomas Crowley); varieties of drug dependence (Dorothy Hatsukami); internal medicine, health care delivery, and clinical epidemiology (Eric B. Larson); cannabinoids and marijuana pharmacology (Billy R. Martin); and cannabinoid neuroscience (Steven R. Childers). Public outreach included setting up a Web site that provided information about the study and asked for input from the public. The Web site was open for comment from November 1997 until November Some 130 organizations were invited to participate in the public workshops. Many people in the organizations--particularly those opposed to the medical use of marijuana--felt that a public forum was not conducive to expressing their views; they were invited to communicate their opinions (and reasons for holding them) by mail or telephone. As a result, roughly equal numbers of persons and organizations opposed to and in favor of the medical use of marijuana were heard from. The study team visited four cannabis buyers' clubs in California (the Oakland Cannabis Buyers' Cooperative, the San Francisco Cannabis Cultivators Club, the Los Angeles Cannabis Resource Center, and Californians Helping Alleviate Medical Problems, or CHAMPS) and two HIV/AIDS clinics (AIDS Health Care Foundation in Los Angeles and Louisiana State University Medical Center in New Orleans). We listened to many individual stories from the buyers' clubs about using marijuana to treat a variety of symptoms and heard clinical observations on the use of Marinol to treat AIDS patients. Marinol is the brand name for dronabinol, which is 9 -tetrahydrocannabinol (THC) in pill form and is available by prescription for the treatment of nausea associated with chemotherapy and AIDS wasting. MARIJUANA TODAY The Changing Legal Landscape In the 20th century, marijuana has been used more for its euphoric effects than as a medicine. Its psychological and behavioral effects have concerned public officials since the drug first appeared in the southwestern and southern states during the first two decades of the century. By 1931, at least 29 states had prohibited use of the drug for nonmedical purposes. 3 Marijuana was first regulated at the federal level by the Marijuana Tax Act of 1937, which required anyone producing, distributing, or using marijuana for medical purposes to register and pay a tax and which effectively prohibited nonmedical use of the drug. Although the act did not make medical use of marijuana illegal, it did make it expensive and inconvenient. In 1942, marijuana was removed from the U.S.

15 Pharmacopoeia because it was believed to be a harmful and addictive drug that caused psychoses, mental deterioration, and violent behavior. In the late 1960s and early 1970s, there was a sharp increase in marijuana use among adolescents and young adults. The current legal status of marijuana was established in 1970 with the passage of the Controlled Substances Act, which divided drugs into five schedules and placed marijuana in Schedule I, the category for drugs with high potential for abuse and no accepted medical use (see Appendix C, Scheduling Definitions). In 1972, the National Organization for the Reform of Marijuana Legislation (NORML), an organization that supports decriminalization of marijuana, unsuccessfully petitioned the Bureau of Narcotics and Dangerous Drugs to move marijuana from Schedule I to Schedule II. NORML argued that marijuana is therapeutic in numerous serious ailments, less toxic, and in many cases more effective than conventional medicines. 13 Thus, for 25 years the medical marijuana movement has been closely linked with the marijuana decriminalization movement, which has colored the debate. Many people criticized that association in their letters to IOM and during the public workshops of this study. The argument against the medical use of marijuana presented most often to the IOM study team was that "the medical marijuana movement is a Trojan horse"; that is, it is a deceptive tactic used by advocates of marijuana decriminalization who would exploit the public's sympathy for seriously ill patients. Since NORML's petition in 1972, there have been a variety of legal decisions concerning marijuana. From 1973 to 1978, 11 states adopted statutes that decriminalized use of marijuana, although some of them recriminalized marijuana use in the 1980s and 1990s. During the 1970s, reports of the medical value of marijuana began to appear, particularly claims that marijuana relieved the nausea associated with chemotherapy. Health departments in six states conducted small studies to investigate the reports. When the AIDS epidemic spread in the 1980s, patients found that marijuana sometimes relieved their symptoms, most dramatically those associated with AIDS wasting. Over this period a number of defendants charged with unlawful possession of marijuana claimed that they were using the drug to treat medical conditions and that violation of the law was therefore justified (the so-called medical necessity defense). Although most courts rejected these claims, some accepted them. 8 Against that backdrop, voters in California and Arizona in 1996 passed two referenda that attempted to legalize the medical use of marijuana under particular conditions. Public support for patient access to marijuana for medical use appears substantial; public opinion polls taken during 1997 and 1998 generally reported percent of respondents in favor of allowing medical uses of marijuana. 15 However, those referenda are at odds with federal laws regulating marijuana, and their implementation raises complex legal questions. Despite the current level of interest, referenda and public discussions have not been well informed by carefully reasoned scientific debate. Although previous reports have all called for more research, the nature of the research that will be most helpful depends greatly on the specific health conditions to be addressed. And while there have been

16 important recent advances in our understanding of the physiological effects of marijuana, few of the recent investigators have had the time or resources to permit detailed analysis. The results of those advances, only now beginning to be explored, have significant implications for the medical marijuana debate. Several months after the passage of the California and Arizona medical marijuana referendums, the Office of National Drug Control Policy (ONDCP) asked whether IOM would conduct a scientific review of the medical value of marijuana and its constituent compounds. In August 1997, IOM formally began the study and appointed John A. Benson Jr. and Stanley J. Watson Jr. to serve as principal investigators for the study. The charge to IOM was to review the medical use of marijuana and the harms and benefits attributed to it (details are given in Appendix D). Medical Marijuana Legislation Among the States The 1996 California referendum known as Proposition 215 allowed seriously ill Californians to obtain and use marijuana for medical purposes without criminal prosecution or sanction. A physician's recommendation is needed. Under the law, physicians cannot be punished or denied any right or privilege for recommending marijuana to patients who suffer from any illness for which marijuana will provide relief. The 1996 Arizona referendum known as Proposition 200 was largely about prison reform but also gave physicians the option to prescribe controlled substances, including those in Schedule I (e.g., marijuana), to treat the disease or relieve the suffering of seriously or terminally ill patients. Five months after the referendum was passed, it was stalled whenarizona legislators voted that all prescription medications must be approved by the Food and Drug Administration, and marijuana is not so approved. In November 1998, Arizona voters passed a second referendum designed to allow physician's to prescribe marijuana as medicine, but this is still at odds with federal law. 8 As of summer 1998, eight states--california, Connecticut, Louisiana, New Hampshire, Ohio, Vermont, Virginia, and Wisconsin--had laws that permit physicians to prescribe marijuana for medical purposes or to allow a medical necessity defense. 8 In November 1998, five states--arizona, Alaska, Oregon, Nevada, and Washington--passed medical marijuana ballot initiatives. The District of Columbia also voted on a medical marijuana initiative, but was barred from counting the

17 votes because an amendment designed to prohibit them from doing so was added to the federal appropriations bill; however, exit polls suggested that a majority of voters had approved the measure. MARIJUANA AND MEDICINE Marijuana plants have been used since antiquity for both herbal medication and intoxication. The current debate over the medical use of marijuana is essentially a debate over the value of its medicinal properties relative to the risk posed by its use. Marijuana's use as an herbal remedy before the 20th century is well documented. 1,10,11 However, modern medicine adheres to different standards from those used in the past. The question is not whether marijuana can be used as an herbal remedy but rather how well this remedy meets today's standards of efficacy and safety. We understand much more than previous generations about medical risks. Our society generally expects its licensed medications to be safe, reliable, and of proven efficacy; contaminants and inconsistent ingredients in our health treatments are not tolerated. That refers not only to prescription and over-the-counter drugs but also to vitamin supplements and herbal remedies purchased at the grocery store. For example, the essential amino acid l- tryptophan was widely sold in health food stores as a natural remedy for insomnia until early 1990 when it became linked to an epidemic of a new and potentially fatal illness (eosinophilia-myalgia syndrome). 9,12 When it was removed from the market shortly thereafter, there was little protest, despite the fact that it was safe for the vast majority of the population. The 1,536 cases and 27 deaths were later traced to contaminants in a batch produced by a single Japanese manufacturer. Although few herbal medicines meet today's standards, they have provided the foundation for modern Western pharmaceuticals. Most current prescriptions have their roots either directly or indirectly in plant remedies. 7 At the same time, most current prescriptions are synthetic compounds that are only distantly related to the natural compounds that led to their development. Digitalis was discovered in foxglove, morphine in poppies, and taxol in the yew tree. Even aspirin (acetylsalicylic acid) has its counterpart in herbal medicine: for many generations, American Indians relieved headaches by chewing the bark of the willow tree, which is rich in a related form of salicylic acid. Although plants continue to be valuable resources for medical advances, drug development is likely to be less and less reliant on plants and more reliant on the tools of

18 modern science. Molecular biology, bioinformatics software, and DNA array-based analyses of genes and chemistry are all beginning to yield great advances in drug discovery and development. Until recently, drugs could only be discovered; now they can be designed. Even the discovery process has been accelerated through the use of modern drug-screening techniques. It is increasingly possible to identify or isolate the chemical compounds in a plant, determine which compounds are responsible for the plant's effects, and select the most effective and safe compounds--either for use as purified substances or as tools to develop even more effective, safer, or less expensive compounds. Yet even as the modern pharmacological toolbox becomes more sophisticated and biotechnology yields an ever greater abundance of therapeutic drugs, people increasingly seek alternative, low-technology therapies. 4,5 In 1997, 46 percent of Americans sought nontraditional medicines and spent over 27 billion unreimbursed dollars; the total number of visits to alternative medicine practitioners appears to have exceeded the number of visits to primary care physicians. 5,6 Recent interest in the medical use of marijuana coincides with this trend toward self-help and a search for "natural" therapies. Indeed, several people who spoke at the IOM public hearings in support of the medical use of marijuana said that they generally preferred herbal medicines to standard pharmaceuticals. However, few alternative therapies have been carefully and systematically tested for safety and efficacy, as is required for medications approved by the FDA (Food and Drug Administration). 2 WHO USES MEDICAL MARIJUANA? There have been no comprehensive surveys of the demographics and medical conditions of medical marijuana users, but a few reports provide some indication. In each case, survey results should be understood to reflect the situation in which they were conducted and are not necessarily characteristic of medical marijuana users as a whole. Respondents to surveys reported to the IOM study team were all members of "buyers' clubs," organizations that provide their members with marijuana, although not necessarily through direct cash transactions. The atmosphere of the marijuana buyers' clubs ranges from that of the comparatively formal and closely regulated Oakland Cannabis Buyers' Cooperative to that of a "country club for the indigent," as Denis Peron described the San Francisco Cannabis Cultivators Club (SFCCC), which he directed. John Mendelson, an internist and pharmacologist at the University of California, San Francisco (UCSF) Pain Management Center, surveyed 100 members of the SFCCC who were using marijuana at least weekly. Most of the respondents were unemployed men in their forties. Subjects were paid $50 to participate in the survey; this might have encouraged a greater representation of unemployed subjects. All subjects were tested for drug use. About half tested positive for marijuana only; the other half tested positive for drugs in addition to marijuana (23% for cocaine and 13% for amphetamines). The predominant disorder was AIDS, followed by roughly equal numbers of members who reported chronic pain, mood disorders, and musculoskeletal disorders (Table 1.1).

19 The membership profile of the San Francisco club was similar to that of the Los Angeles Cannabis Resource Center (LACRC), where 83% of the 739 patients were men, 45% were years old, and 71% were HIV positive. Table 1.2 shows a distribution of conditions somewhat different from that in SFCCC respondents, probably because of a different membership profile. For example, cancer is generally a disease that occurs late in life; 34 (4.7%) of LACRC members were over 55 years old; only 2% of survey respondents in the SFCCC study were over 55 years old. Jeffrey Jones, executive director of the Oakland Cannabis Buyers' Cooperative, reported that its largest group of patients is HIV-positive men in their forties. The secondlargest group is patients with chronic pain. Among the 42 people who spoke at the public workshops or wrote to the study team, only six identified themselves as members of marijuana buyers' clubs. Nonetheless, they presented a similar profile: HIV/AIDS was the predominant disorder, followed by chronic pain (Tables 1.3 and 1.4). All HIV/AIDS patients reported that marijuana relieved nausea and vomiting and improved their appetite. About half the patients who reported using marijuana for chronic pain also reported that it reduced nausea and vomiting. Note that the medical conditions referred to are only those reported to the study team or to interviewers; they cannot be assumed to represent complete or accurate diagnoses. Michael Rowbotham, a neurologist at the UCSF Pain Management Center, noted that many pain patients referred to that center arrive with incorrect diagnoses or with pain of unknown origin. At that center the patients who report medical benefit from marijuana say that it does not reduce their pain but enables them to cope with it. Most--not all--people who use marijuana to relieve medical conditions have previously used it recreationally. An estimated 95% of the LACRC members had used marijuana before joining the club. It is important to emphasize the absence of comprehensive information on marijuana use before its use for medical conditions. Frequency of prior use almost certainly depends on many factors, including membership in a buyers' club, membership in a population sector that uses marijuana more often than others (for example, men years old), and the medical condition being treated with marijuana (for example, there are probably relatively fewer recreational marijuana users among cancer patients than among AIDS patients). Patients who reported their experience with marijuana at the public workshops said that marijuana provided them with great relief from symptoms associated with disparate diseases and ailments, including AIDS wasting, spasticity from multiple sclerosis, depression, chronic pain, and nausea associated with chemotherapy. Their circumstances and symptoms were varied, and the IOM study team was not in a position to make medical evaluations or confirm diagnoses. Three representative cases presented to the IOM study team are presented in Box 1.1; the stories have been edited for brevity, but each case is presented in the patient's words and with the patient's permission.

20 The variety of stories presented left the study team with a clear view of people's beliefs about how marijuana had helped them. But this collection of anecdotal data, although useful, is limited. We heard many positive stories but no stories from people who had tried marijuana but found it ineffective. This is a fraction with an unknown denominator. For the numerator we have a sample of positive responses; for the denominator we have no idea of the total number of people who have tried marijuana for medical purposes. Hence, it is impossible to estimate the clinical value of marijuana or cannabinoids in the general population based on anecdotal reports. Marijuana clearly seems to relieve some symptoms for some people--even if only as a placebo effect. But what is the balance of harmful and beneficial effects? That is the essential medical question that can be answered only by careful analysis of data collected under controlled conditions. CANNABIS AND THE CANNABINOIDS Marijuana is the common name for Cannabis sativa, a hemp plant that grows throughout temperate and tropical climates. The most recent review of the constituents of marijuana lists 66 cannabinoids (Table 1.5). 16 But that does not mean there are 66 different cannabinoid effects or interactions. Most of the cannabinoids are closely related; they fall into only 10 groups of closely related cannabinoids, many of which differ by only a single chemical moiety and might be midpoints along biochemical pathways--that is, degradation products, precursors, or byproducts. 16,18 9 -tetrahydrocannabinol ( 9 - THC) is the primary psychoactive ingredient; depending on the particular plant, either THC or cannabidiol is the most abundant cannabinoid in marijuana (Figure 1.1). Throughout this report, THC is used to indicate 9 -THC. In the few cases where variants of THC are discussed, the full names are used. All the cannabinoids are lipophilic--they are highly soluble in fatty fluids and tissues but not in water. Indeed, THC is so lipophilic that it is aptly described as "greasy." Throughout this report, marijuana refers to unpurified plant extracts, including leaves and flower tops, regardless of how they are consumed--whether by ingestion or by smoking. References to the effects of marijuana should be understood to include the composite effects of its various components; that is, the effects of THC are included among the effects of marijuana, but not all the effects of marijuana are necessarily due to THC. Discussions concerning cannabinoids refer only to those particular compounds and not to the plant extract. This distinction is important; it is often blurred or exaggerated. Cannabinoids are produced in epidermal glands on the leaves (especially the upper ones), stems, and the bracts that support the flowers of the marijuana plant. Although the flower itself has no epidermal glands, it has the highest cannabinoid content anywhere on the plant, probably because of the accumulation of resin secreted by the supporting bracteole (the small leaf-like part below the flower). The amounts of cannabinoids and their relative abundance in a marijuana plant vary with growing conditions, including humidity, temperature, and soil nutrients (reviewed in Pate, ). The chemical stability of cannabinoids in harvested plant material is also affected by moisture, temperature, sunlight, and storage. They degrade under any storage condition.

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